The HDAC6 gene that we propose to study in this project is a novel therapeutic candidate emerged from the burgeoning field of epigenetics. Histone deacetylases (HDACs) are the therapeutic targets of a novel class of anticancer therapies called HDAC inhibitors. Non-selective inhibitors of histone deacetylases, which promote protein hyperacetylation in the brain, have demonstrated consistent behavioral activity across various rodent models, including models of affective disorders and antidepressant response. Although most studies, so far, have interpreted this antidepressant-like activity in the context of chromatin-remodeling mechanisms (ie the canonical role of HDACs) it is now well established that the influence of protein acetylation on cellular processes extends far beyond transcriptional regulation. In fact, certain deacetylases, of which HDAC6 is a prominent example, are involved primarily in non-histone functions. These functions comprise, for instance, the regulation of HSP90's chaperone activity, an important component of steroid receptors signaling. Through this mechanism, HDAC inhibitors have recently been shown to blunt Glucocorticoid Receptor (GR) function, one of the main receptors for stress steroid hormones. Our preliminary data indicate that HDAC6 is enriched in the serotonin system, the primary target of most antidepressants currently used in the clinic. Here, we propose to test the hypothesis that inhibition of HDAC6 constitutes a candidate therapeutic mechanism for antidepressant and pro-resilience interventions through focused inhibition of GR signaling within the serotonergic system. To test this hypothesis we propose the following aims. Our Aim I is to conduct a comprehensive regional and cellular mapping of HDAC6 mRNA and protein in the mouse brain, and to start evaluating the pattern of HDAC6 expression in the human brain. Our Aim II is to evaluate the behavioral consequences of HDAC6 manipulations in 5-HT system. Here we will combine pharmacological approaches with serotonin-specific gain and loss of function of HDAC6 in the live animal. Consequences of these manipulations will be examined in a battery of tests measuring resilience to chronic stress as well as sensitivity to acute and chronic effects of antidepressants. Our Aim III is to examine HDAC6's influence on GR signaling in 5-HT neurons. Here, we will use a combination of in vivo and cell culture-based assays to characterize the effect of HDAC6 KO and HDAC6 pharmacological inhibition on HSP90 acetylation, GR translocation and GR-mediated gene regulation. The goals of this project connect in 2 major ways with areas of high priority defined by the NIH in the field of Neuroscience and Basic Behavioral Science. First, this proposal will increase our understanding of the fundamental mechanisms of complex social behavior relevant to the socio-affective component of depressive symptomatology. Second, we hope to validate HDAC6 as a new molecular target relevant to the treatment of mental disorders.